1. Field of the Invention
The present invention relates to the fields of biomedical engineering and the chemistry of wound healing and biological glues. More specifically, the present invention relates to a novel porous tissue scaffoldings, which enhance wound healing and also serve as biological glues.
2. Description of the Prior Art
Skin injuries are a primary cause of death in North American for people between the ages of 1 and 44. Although different in etiology and prognosis, the treatment goal for all types of wounds is the same: skin regeneration. Two of the most common skin wounds are skin ulcers and bums. The most prevalent skin ulcers are pressure ulcers, diabetic ulcers, and venous statis ulcers.
There are various types of skin wounds. For example, pressure ulcers, caused by prolonged excessive pressure, and burns, caused by excessive heat, are significant problems in this society. Both heal in the clinical setting, once the causative agent is removed, although improving the speed and quality of healing is highly desirable.
Pressure ulcers are found in 20-30% of the approximately 200,000 spinal cord injury patients, 3-15% of nursing home residents or elderly patients, and in 3-11% of acute injury patients; for a total of approximately 800,000 patients per year. It is estimated that patients with pressure ulcers incur at least an additional $15,000/year in health care costs with estimates as high as $58,000. Enhancing the rate of regenerative healing would reduce the likelihood and effect of secondary complications.
It has been estimated that more than 500,000 persons are treated in a hospital emergency department each year due to thermal injury. Additionally, as many as 70,000 to 100,000 are hospitalized, and of these, 10,000 to 12,000 will die. Development of more active treatments can accelerate healing in these acute wounds as well as chronic non-healing; wounds and reduce morbidity and mortality associated with these skin wounds. Although little is known about the relative importance of and the relationships among the factors which enhance regeneration, it appears that the use of growth factors is one of the most powerful and direct methods presently, available to enhance and control wound healing. A degradable matrix used to deliver the growth factor, not only protects the growth factor which has a short in vivo half-life until release, but also serves as a scaffold for tissue formation.
Many investigators have examined ways to enhance and control healing. Healing is affected by altering the wound environment (oxygen, magnetic fields, stress, location, etc.) or wound biochemical activity (growth factors, growth hormone, and other biochemical agents). For skin wounds. rapid regeneration of connective tissue and the overlying epidermis is the goal. When a wound dressing or implant is used, wound healing can be altered by changing the implant configuration (pore size, porosity, fiber diameter etc.), the implant surface (composition, charge, surface energy, etc.), the implant biochemical activity (incorporation of growth factors or other biochemical factors), or the implant physical activity (degradation rate and drug delivery rate). Implants, used in the skin as tissue scaffolds, should be degradable to allow complete skin regeneration. When used beneath grafted skin, they should also allow rapid blood vessel infiltration and re-attachment (angiogenesis) between the graft and the underlying, tissue bed. In both cases, the interconnected porosity is critical for angiogenesis, since blood vessels require at least 40 mm pores to grow into a biomaterial. Additionally, an adhesive biodegradable matrix would help speed up the surgical procedure, of skin grafting, while enhancing juxtaposition between a skin graft and the underlying tissue bed.
One such biodegradable matrix is fibrin. Fibrin derived from blood has been used as a tissue adhesive. It is generally supplied as a two-component kit consisting of human-source fibrinogen/Factor XIII and bovine thrombin/CaCl2. These fibrin sealants have been used since 1972 in Europe where a commercial version is presently available. No commercial product is available in the United States, and studies have been done using autologous or single donor preparation. Clinically, the fibrin matrix has been used as a hemostatic agent, for tissue anastomosis, as a fluid barrier, as a drug delivery vehicle, and as a tissue scaffold. Fibrin sealant used for skin grafting has been shown to increase attachment strength, to the wound bed, compared with staples, leading to less seroma formation and wound contraction.
Another biodegradable matrix suitable for use in wound healing and as a biological scaffold is modified polyethylene glycol (PEG) crosslinked albumin.
Using natural biomaterials, such as fibrin and albumin, delivery of a biochemical agent can be accomplished in a number of different ways. For example, the fibrin or PEG crosslinked albumin can be impregnated with the biochemical factor or agent; the agent can be attached to the polymer chain or it can be included through intra-fibril entrapment. Certain growth factors like FGF can bind to these polymers, like fibrin, Otherwise, the growth factors need to be attached through various linkages. When the growth factor is bound, it is released only when the fibrin or albumin degrades. Since the degradation is cellular, the growth factor release is controlled by the rate of phagocytic cellular infiltration and is thus under biofeedback control. Additionally, the degradation is at the wound edge and thus gives the appropriate gradient to stimulate further angiogenesis and tissue healing.
The use of a degradable matrix to deliver a biochemical agent, such as a growth factor, protects the growth factor until release, since it seems to have a short half-life in vivo even in the presence of heparin. This short half-life in vivo is potentially a problem for clinical studies using topical administration of growth factors, besides the inconvenience and added personnel expense.
Fibroblast growth factor (FGF), has been shown to induce angiogenesis. The mitogenic, chemotactic and differentiation properties of this growth factor suggests that it is involved in embryonic development and is probably a major trophic factor operating at all stages of embryogenesis. Unlike other growth factors such as platelet derived growth factor (PDGF), transforming growth factor, and epidermal growth factor (EGF), FGF can stimulate in vivo as well as in vitro proliferation of all cell types involved in wound healing. In, vitro studies have demonstrated that FGF inhibits contraction while enhancing wound healing. The inhibition of contraction may have therapeutic implications in the prevention of contracture scars. FGF has also been shown to increase graft survival by stimulation of epithelialization by cultured keratinocytes and vascularization in the wound bed in athymic mice.
Both basic FGF (FGF-2) and acidic FGF (FGF-1) are extremely angiogenic in vivo and mitogenic for fibroblasts in vitro. A preferential response by keratinocytes to FGF-1 in either the presence or absence of heparin, compared to FGF-2, has been reported. Stimulation of angiogenesis, granulation tissue formation and neo-epithelialization as well as increased wound strength, with increased cellularity and collagen deposition, without promoting contraction have been demonstrated in response to FGF-1, in vivo, in dermal wounds.
Clinical measures of wound healing include estimates of skin graft take, area healed, time to subjective healing, and length of hospital stay. Even the more quantitative measurement of change in surface area healed suffers from variability due to the effect of wound size on healing rate. The larger the wound, the more tissue that can be laid down in each time period, and the larger the change in volume or surface area. The optimal parameter to assess rate of healing should be independent of wound size. A measure that fits this description is the change in average wound diameter. It has been shown that the epidermal migration rate is relatively constant at approximately 1-2 mm/week.
Additionally, skin grafts secured with sutures or staples are commonly used in the treatment of patients with third degree bums. The associated potential for fluid collection between the wound surface and the grafted skin, which comprises the viability of the graft, may be minimized by attaching grafts using naturally occurring glues. Also, these glues provide a scaffold for tissue and can be impregnated with growth factors and antibiotics to enhance wound healing. In addition, the rate of degradation can often be controlled by biofeedback. Fibrin glue is a popular choice for applications of this nature and has recently been approved for hemostatic uses in the U.S. The current cost ($300/2 ml) has precluded the widespread use of this product in the U.S. Hence, applicants are examining other commercially viable alternatives. One such possibility is albumin glue, which is FDA approved, does not have the disease concerns associated with fibrin, and is considerably cheaper.
The prior art is deficient in the lack of effective means of facilitating the repair or regeneration of biological structures such as in the healing of wounds. The present invention fulfills this longstanding need and desire in the art.
Therefore, it is an object of the present invention to design biodegradable scaffold or porous materials which are capable of locally delivering at least one agent including fibroblast growth factor (FGF-1). The present invention also provides a bioadhesive scaffold or porous material including albumin, a polyethylene crosslinking agent, and a modifying agent incorporated into the bioadhesive material.